Targeting the BspC-vimentin interaction to develop anti-virulence therapies during Group B streptococcal meningitis

Bacterial infections are a major cause of morbidity and mortality worldwide and the rise of antibiotic resistance necessitates development of alternative treatments. Pathogen adhesins that bind to host cells initiate disease pathogenesis and represent potential therapeutic targets. We have shown previously that the BspC adhesin in Group B Streptococcus (GBS), the leading cause of bacterial neonatal meningitis, interacts with host vimentin to promote attachment to brain endothelium and disease development. Here we determined that the BspC variable (V-) domain contains the vimentin binding site and promotes GBS adherence to brain endothelium. Site directed mutagenesis identified a binding pocket necessary for GBS host cell interaction and development of meningitis. Using a virtual structure-based drug screen we identified compounds that targeted the V-domain binding pocket, which blocked GBS adherence and entry into the brain in vivo. These data indicate the utility of targeting the pathogen-host interface to develop anti-virulence therapeutics. Author summary Group B Streptococcus (GBS) is the leading cause of bacterial neonatal meningitis. GBS utilizes a surface adhesin known as BspC to interact with vimentin expressed by the endothelial cells that form the blood-brain barrier (BBB). The BspC–vimentin interaction promotes GBS adherence to the BBB and facilitates the pathogenesis of GBS meningitis. Here we identified the vimentin-binding pocket of BspC within the variable (V-) domain and showed that an intact and accessible vimentin-binding pocket was required for GBS virulence. We used a virtual structure-based screen to identify compounds that could block the V-domain pocket and confirmed that chemically targeting the pocket could limit GBS adherence to the BBB as well as entry into the brain using our murine model of meningitis. Collectively, these results lay the foundation for development of novel anti-virulence therapies to prevent GBS pathogenesis.